Clinical translation of liquid biopsy in early cancer screening: biofluid selection, model construction, and clinical validation

Global cancer incidence continues to rise, underscoring the urgent need for effective early detection strategies. Liquid biopsy shows promise as a minimally invasive approach, yet only a limited number of assays have successfully transitioned from research to clinical practice. This review examines the critical decisions and challenges encountered along the translational pathway for liquid biopsy based early cancer screening, covering biofluid selection, biomarker characteristics, multi-omics integration, model construction, and the hierarchy of clinical evidence. We highlight the importance of biologically driven complementarity in biomarker combination, rigorous control group design, and prospective real-world validation, while also identifying key gaps that currently constrain clinical adoption. Collectively, these considerations aim to inform more efficient development strategies and help bridge the gap between technological innovation and clinically impactful tests.